I. Dioxins and furans
1.Pollution source
Dioxins, such as polychlorinated biphenyls-P-dioxins (PCDD) and furans, such as polychlorinated biphenyls-P-furans (PCDF), are synthetic halogenated aromatic hydrocarbons (Table 2, Supplementary Figure 1e). PCDD and PCDF are ubiquitous environmental pollutants and are wastes formed during the production of pesticides, wood pulp bleaching, and waste incineration.
Under the 2001 Stockholm Convention, PCDD and PCDF were banned worldwide, but some products produced before the ban were enacted are still present. Similarly, PCDD and PCDF are present in the environment and in humans due to their resistance to biodegradation processes. the half-lives of PCDD and PCDF range from 2 to 15 years. The vast majority of human exposure to dioxins comes from the consumption of some products such as meat, milk, eggs and fish, where dioxins accumulate in the fat of the animals that produce these products.
The biological effects of dioxins are mediated primarily through the ligand-activated transcription factor aryl hydrocarbon receptor (AHR). This transcription factor regulates gene expression by binding to the AHR nuclear translocator (ARNT) through a dioxin-responsive element in the DNA sequence. The World Health Organization (WHO) has developed a toxicity equivalence factor scale based on the agonistic effects of various chemicals on the AHR. Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent and well-studied agonist molecule. This toxicity equivalence factor represents the relative AHR-mediated efficacy of PCDD and PCDF compared to TCDD.
PCDD-mediated organ damage and cardiotoxicity are associated with AHR activation. Although these effects were first characterized for dioxins and polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) have also been elucidated in developing zebrafish embryos to induce cardiotoxicity via an AHR mechanism.
2. Metabolism
PCCD and PCDF are readily absorbed through the digestive tract and their absorption is facilitated by ingestion of fatty foods. the lipophilic nature of PCCD and PCDF makes them slow to be excreted in bile and urine. the CYP1A1 enzyme is a well-studied AHR/ARNT target and is often used as a marker for AHR activation, through which these compounds are toxic. The mechanism of intrarenal PCCD and PCDF processing has not been fully elucidated.
3. Albuminuria
No studies have provided information on the effects of PCDD and PCDF on albuminuria in healthy subjects (Table 3).NHANES
1999C2004 study included 2588 cases of diabetes defined as diabetic nephropathy by the presence of microalbuminuria (albumin/creatinine ratio >30 mg/g) or massive albuminuria, and found that three different PCDF
serum concentrations were associated with diabetic nephropathy. At least 4 of the 23 chemicals analyzed in this study had elevated serum levels with a dominant ratio OR for the development of diabetic nephropathy ofwas 7.00 (95% CI,
1.80C27.20) and the OR for the development of diabetes without nephropathy was 2.13 (95% CI, 0.95C4.78).
4. eGFR
Medium to high dioxin exposure was associated with hyperalgesia (Table 5). A cross-sectional study enrolling 1531 healthy adults living near a PCQ plant no longer in use found a one-way strong negative association between PCDD exposure and eGFR. Compared to the lowest quartile group, toxicant exposure in the highest quartile group resulted in a 14.8 reduction in eGFR for men and women, respectively
The correlation between low-level dioxin exposure and renal function in healthy adults or children without occupational exposure remains unclear.
5. Blood pressure
A study enrolling 1490 non-diabetic adults living in a dioxin-contaminated area showed that elevated serum dioxin levels were associated with increased diastolic blood pressure. Furthermore, the prevalence of hypertension was associated with serum PCCD and PCDF levels in adults with suspected dioxin exposure due to living near uncontrolled abandoned hazardous dumps. A U.S. study that included 721 adults who were far from a clear source of contamination and did not have diabetes also found a moderate association between dioxin exposure and hypertension. This finding has been confirmed in a follow-up study of adults living in Japan (Table 4).
6. Uric acid concentration
The previously discussed study of adults living near a disused pentachlorobenzone plant also found an increase in serum uric acid concentrations in healthy men in the highest quartile of toxicant exposure of 35
μmol/l (0.59 mg/dl), but no increase in uric acid concentrations in women. Also, men with serum dioxin concentrations above the reference value had a 2.2-fold increased risk of hyperuricemia. Nose, Osaka, Japan
Bika Center incinerator is heavily contaminated with PCCD, and similar observations were made on 94 workers in it. The risk of hyperuricemia was also increased in adults with only basal dioxin exposure. Based on specific dioxin compound exposure, NHANES
2003C2004 survey of 1331 adults had an adjusted hyperuricemia advantage ratio OR of 2.3 to 3.0 (Table 6).
II. Polycyclic aromatic hydrocarbons
1.Pollution source
Polycyclic aromatic hydrocarbons (PAH) are composed of more than 100 different chemicals that consist purely of carbon and hydrogen atoms arranged in multiple aromatic rings. Most PAHs are formed during the incomplete combustion of coal, oil and gas, and can also come from other organics such as tobacco and wood charcoal grills. Although exposure to these compounds occurs primarily in working environments, such as chemical plants and coke (fuel) growers, the popularity of motor vehicles with internal combustion engines and increased production activities have led to significant environmental exposures, particularly in urban areas.
Incomplete combustion of carbon-based fuels produces oxidized PAH, which is highly mutagenic and carcinogenic. Benzoa pyrene is a well-studied PAH and a major carcinogen in tobacco. PAH has been detected in the serum of pregnant nonsmokers residing in the New York metropolitan area at exposure levels associated with outdoor hours, house heating, and indoor incense burning. Urinary PAH excretion rates were reduced in children living in New York under traffic air pollution laws.
2. Metabolism
PAH is activated by CYP1A1, and polymorphisms in the gene encoding this enzyme have been associated with changes in PAH metabolism. Glutathione-S-transferases are involved in PAH binding to glutathione, and genetic variation in these proteins contributes to differential PAH metabolism.PAH exposure was accompanied by the detection of benzo-a-pyrene-diol epoxides forming adducts with albumin and DNA. The formation of these chemical adducts may provide a more accurate evaluation of PAH exposure and potential nephrotoxicity.
3. eGFR
NHANES
The 2003C2004 survey studied 999 subjects and found that high PAH exposure resulted in a 3.6-fold advantage ratio of elevated C-reactive protein levels. Considering the effect of inflammatory response in atherosclerosis, these results are consistent with the role of PAH in cardiovascular disease. However, few studies have elucidated the effects of PAH exposure on glomerular (eGFR and albuminuria) and tubular damage (Table 5).
Balkan endemic nephropathy is a chronic tubulointerstitial disease that increases the risk of urothelial cancer, which is caused by PAH exposure. PAH contamination in drinking water is caused by the infiltration of lignite and coke plants into the drinking water supply system. PAH contamination of drinking water is associated with substantial renal disease and urologic malignancies. Epidemiological studies and preclinical investigations are needed to confirm the role of PAH in Balkan endemic nephropathy.
4. Blood pressure
A small single-center study enrolling 88 nonsmoking adult Belgian residents found that selected serum PAH compound levels were linearly associated with systolic and pulse pressure. Large cohort studies are needed to further confirm the correlation between PAH exposure and risk of hypertension (Table 4).
III. Polychlorinated biphenyls
1. Source of contamination
Polychlorinated biphenyls (PCBs) are molecules composed of two benzene rings on a ring skeleton with different degrees of saturation of chlorine groups. Due to the different degrees of saturation of chlorine groups, PCBs include 209 unique related chemicals (Table 2, Supplementary Figure 1g). PCBs were widely used in capacitors and coolants in electrical equipment until it was recognized that it could persist in the environment and be bioaccumulative and toxic in animals and humans. Subsequently, the U.S. and Stockholm conventions banned PCB production in 1997 and 2001, respectively, but PCB is widespread in the population due to its persistence in the environment, incomplete disposal, and continued use of PCB-containing products.
In the 1970s, the Hudson River was contaminated with PCBs due to the disposal of products containing PCBs. As a result, the river was listed by U.S. federal law as the largest cleanup site for the U.S. Environmental Protection Agency’s Toxic Waste Dump Pollution Removal Fund program, which aims to clean up areas contaminated with hazardous substances. As a result, the station announcement cautions against the consumption of fish from the waters. Serum PCB levels for non-occupationally exposed residents in the United States were 0.6C4.0
ng/g (adolescents) and 8.9C60.8
ng/g (>60 years old). Serum PCB levels in residents who consumed large amounts of fish food from contaminated waters were several times higher than those without PCB exposure and comparable to PCB factory workers.
2.Metabolism
PCB metabolism mainly in the liver, first must undergo hydroxylation, increasing molecular polarity, and then excreted through the bile. the rate of metabolism of PCB depends on the degree of chlorination of the same. PCB metabolism also produces toxic active ingredients, such as aromatic oxides, which are excreted after enzymatic digestion, or the formation of toxic adducts.
3. Albuminuria
There are no data reporting the effect of PCB on proteinuria in people without kidney disease. nHANES
1999C2004 study included 2588 diabetic patients and found that those with high levels of PCB-like substance exposure had an increased risk of diabetic nephropathy (Table 3).
4. eGFR
An accident at the Bloomington power capacitor manufacturing plant in the United States resulted in the discharge of PCBs into the municipal wastewater treatment system. PCB compounds were detected in sewage sludge used as fertilizer. A limited follow-up study found that only PCB-exposed sewage workers had elevated serum PCB levels and did not find a correlation between PCB serum concentrations and renal function, but no large-scale investigations have examined the effects of PCB on renal function or albuminuria (Table 5).
5, blood pressure
High serum PCB levels were confirmed to be associated with elevated systolic and diastolic blood pressure in residents near pesticide plants producing PCBs (Table 4). correlation between PCB serum levels and blood pressure was also confirmed in non-occupationally exposed populations.
6, NHANES
1999C2002 survey study examined serum concentrations of different PCB substances in 2556 adults11 and found an increased risk of hypertension for seven compounds with a maximum dominance ratio of 2.45. About 25% of the population was found to have elevated levels of one or more PCBs, with a dominance ratio of 1.84 for elevated blood pressure. a similar study from the same NHANES cohort included 524 adults and found that the level of PCB exposure was significantly associated with the incidence of new-onset hypertension in men. A cluster analysis of NHANES
1999C2004 participants using cluster analysis to independently evaluate the study also confirmed the association between PCB and hypertension.
The PIVUS study also confirmed the association between PCB serum levels and blood pressure in 70-year-old Swedish seniors. This cohort study follow-up investigation explained the correlation between PCB exposure and left ventricular systolic and diastolic dysfunction. Moreover, the NHANES
1999C2008 study investigated adults over 20 years of age in the United States. The results found that while lead exposure had the greatest predictive value for diastolic and mean blood pressure, PCB serum levels had the greatest predictive value for systolic blood pressure. A study of Inuit adults living in Greenland and Canada reported the correlation between high serum PCB levels due to fish product consumption and increased risk of hypertension.
7, uric acid concentration
An industrial accident occurred in Japan in 1968, causing massive PCB exposure. PCB serum levels were directly related to uric acid concentrations, and high PCB concentrations were associated with an increased risk of hyperuricemia (Table 6).
IV. Implications for the developing world
This review has focused primarily on the effects of environmental chemicals on populations in affluent, developed countries. However, these molecules discussed in the text may also have an impact on kidney disease in developing regions. Over the past decade, there has been a growing recognition of the major health problem of the CKD epidemic in Central America, called “Mesoamerican nephropathy”. This disease occurs mainly in tropical agricultural areas along the Pacific coast. Similar endemic outbreaks of CKD among farmers in the North Central Province of Sri Lanka have also been documented.
There are some reports on the potential role of cadmium, arsenic and pesticide exposure in the development of CKD among Sri Lankan farmers, but there are some conflicting results in these reports. Patients who developed CKD in both locations were predominantly male and had mild symptoms including mildly elevated blood pressure, small amounts of proteinuria, non-inflammatory urinalysis findings and azotemia (abnormally elevated levels of nitrogenous compounds in the blood).
There are several hypotheses to explain this multifactorial disease, including recurrent dehydration, polyol-fructokinase, and activation of the pressor pathway. There is no conclusive evidence linking Mesoamerican nephropathy to certain drugs such as pesticides, herbal toxicity, heavy metals, or NSAIDs, but the role of environmental chemicals, including pesticides, in this disease has not been systematically elucidated.
Considering that these results were obtained in developed countries with endemic exposure, these environmental chemicals discussed in this paper may also be contributing factors to this epidemic outbreak of CKD. In some developing countries, regulatory systems to control the use of pesticides with hazardous compounds are not routinely enforced, or rules and standards for workforce health protection are poorly enforced. The issue of environmental chemical exposure is a very urgent problem for these countries.
V. Limitations of published reports
1. Cross-sectional study data
Much of the literature on the effects of environmental chemicals on the heart and kidneys is derived from cross-sectional study data. These data relate chemical exposure to the development of the outcome of interest. Most studies have been single assays, with no series of specimens collected for testing. For persistent organic compounds that maintain stable serum levels over time (e.g., PFAA), single assays are not a major concern, but for short half-life molecules such as BPA and phthalates, single assays are an issue. Short-term changes in exposure can significantly affect the urinary excretion rate of these compounds and may mislead the classification of long-term exposure levels.
2. Acute exposure vs. chronic exposure
The nature of environmental chemical exposure can be either acute or chronic in nature. The data we report in this review either originate from after industrial exposure, presumably chronic, or from after a major accident, which may be a high level of acute exposure. However, most of the published studies are cross-sectional in design and do not distinguish between short-term and long-term organic pollutant exposures. Prospective cohort studies using serial biological sample collections are needed to elucidate this important issue. Moreover, no studies have explored in detail the outcomes of multiple different types of chemical exposures, which also requires prospective sample collection with simultaneous detection using multiple analytical methods.
3. Biomarkers of kidney injury
No standardized protocols have been designed to evaluate the effects of environmental chemicals on renal parameters such as albuminuria, eGFR, blood pressure, and serum uric acid concentrations. Therefore, all effects of all types of compounds have not been comprehensively studied. Specific markers of glomerular damage (e.g., podocyte excretion rate) and tubular damage (e.g., NGAL, KIM-1, and IL-18) can also be studied, but these markers do not identify the cause of renal damage and are not specific for environmental chemical exposure. However, abnormalities in serum concentrations and excretion rates of these biomarkers can precede routine clinical tests such as serum creatinine concentrations and are sensitive for the detection of acute kidney injury and CKD. Moreover, these biomarkers can accurately detect the site of renal damage due to environmental toxicants.
Currently, these marker tests are not routinely performed because they are cross-sectional observational cohort studies. Future work in this area should incorporate these novel biomarkers in order to fully elucidate the effects of organic pollutants on kidney injury and dysfunction.
VI. Reverse causality
Many of the organic chemicals described in this paper are excreted through the kidneys. According to the concept of reverse causality, serum levels of organic chemicals may be the result of other factors leading to a decrease in GFR. Moreover, a primary decrease in GFR should cause a decrease in the excretion of organic pollutants. For this reason, some investigators have devalued the data from
NHANES data and refute the causal effect of environmental chemicals on renal function.
Important questions were elaborated using a variety of statistical analyses including multivariate analysis. Prospective longitudinal cohort studies are next needed to confirm findings obtained from cross-sectional studies supported by clinical data. Such an analysis would require serial collection of environmental chemical samples and testing of renal function to precisely depict the association between environmental toxicants and renal function. In this way, the impact of environmental chemicals as variable risk factors on albuminuria, hypertension, hyperuricemia, and CKD can be determined.
VII. Potential mechanisms of injury
1. Oxidative stress
No prospective or interventional studies have confirmed the correlation between environmental chemicals and potential cardiorenal injury. Physiological plausibility first requires linking these two phenomena. Oxidative stress is the primary pathophysiological mechanism that generates cardiometabolic risk and renal injury, and environmental chemical exposure can induce oxidative stress. Lipid peroxidation induces cellular damage and inflammation, and oxidative stress interferes with endothelial diastolic nitric oxide, thereby promoting vasoconstriction, platelet aggregation, and inflammatory cytokine release.
In glomerular podocytes in an animal model of CKD, oxygen radical production is increased. Excessive oxidative stress alters the cytoskeleton of the podocyte, leading to albuminuria, podocyte loss and tubular damage, which are the main pathological changes in the progression of primary glomerulopathy. Various patients with CKD secondary to oxidative stress develop tubulointerstitial fibrosis, which is a better predictor of progressive renal decompensation and prognosis than glomerular lesions.
Environmental chemicals such as BPA, phthalates and biphenyls have been shown to potentially increase cardiometabolic risk, a risk that is not associated with an increased risk of obesity. Animal studies have shown that BPA induces oxidative stress and inhibits the release of lipocalin from human adipose tissue. Experimental studies have found that phthalate metabolites promote the release of IL-6 and increase the expression of neutrophil integrins. Biomarkers of phthalate exposure were also associated with elevated oxidative stress markers such as C-reactive protein, γ-glutamyltransferase, and malondialdehyde and 8-hydroxydeoxyguanosine.
Cell culture showed that microvascular endothelial cells exposed to PFAA increased the production of reactive oxygen clusters, induced endothelial permeability, and played a key role in ischemic kidney injury. Exposure of animals to PBDE induces oxidative stress-mediated hepatotoxicity and nephrotoxicity.PAH is a strong oxidative stressor that enhances lipid oxidation and causes inflammation.PAH also decreases nitric oxide production in human coronary endothelial cells and promotes vasoconstriction, platelet adhesion and inflammatory cytokine release.
As shown above, oxidative stress may be a common pathway mediating renal injury associated with environmental chemical exposure. This mechanism is biologically plausible and will be further confirmed when the adverse effects of these chemicals are examined. Other dysfunctions may contribute to the adverse cardiorenal effects produced by these compounds, including the effects of variable patient factors such as obesity (Figure 1).
2. Intrauterine environment
The “saving genetic phenotype” hypothesis suggests that early life is adapted to the environment of poor nutritional conditions in the uterus, resulting in maladaptive conditions outside the uterus, and the ability to obtain energy outside the uterus leads to obesity. This effect can occur in childhood and contributes to an increased risk of cardiometabolic and renal disease later in life. There is a hypothesis that
Prenatal environmental oxidative stressor exposure increases cardiac and renal risk through intrauterine maladaptation. The association between phthalates and low birth weight and the correlation between elevated maternal BPA levels and lower estimated fetal weight are consistent with this hypothesis.
Several classes of compounds have been studied regarding the effects of organic pollutants during human development. Prenatal BPA
exposure may increase the risk of respiratory disease in childhood. Maternal prenatal phthalate exposure (based on urinary excretion rates) and PAH (based on maternal and neonatal cord blood serum) exposure have been associated with psychiatric, psychological, and behavioral changes in young children at age 3 years.
A review included eight epidemiological studies, six of which were non-occupational exposure studies and two of which were occupational exposure studies. Results found inconsistent correlations between maternal blood and or cord blood PFOS and PFOA concentrations and birth weight or other anthropometric measurements such as head circumference and developmental key parameters at 6 and 18 months of age. Some studies have documented adverse pulmonary and cognitive function effects of prenatal organic pollutant exposure, but no studies have examined the effects of fetal or infant organic pollutant exposure on kidney structure or function.
VIII. Conclusion
The effects of environmental chemicals on GFR described in this review are unlikely to cause clinically significant adverse effects. However, prolonged cumulative exposure to a range of compounds, combined with age-related renal decompensation and other comorbidities, may accelerate deterioration of renal function and progression to CKD. There are also only moderate effects on albuminuria, which may reflect general endothelial dysfunction rather than alterations in the glomerular filtration barrier. Regardless of the underlying mechanism, changes in small amounts of albuminuria due to environmental chemicals are associated with an increased risk of cardiovascular events.
Moderate changes in blood pressure to population blood pressure levels may also be associated with an increased rate of cardiovascular events. Worsening hyperuricemia after toxicant exposure may cause hypertension, exacerbate endothelial dysfunction, and exert effects in conjunction with the metabolic syndrome. These alterations synergistically may increase an individual’s lifetime risk of developing CKD.
The reduction in environmental chemical exposure that could be achieved through a comprehensive revision of regulations governing the use of these compounds would have substantial economic benefits, almost comparable to the cost of preventing cardiac and renal disease. The annual cost of BPA-related cardiovascular disease in the United States is estimated to be $1.5 billion.
Importantly, the adverse cardiorenal effects of environmental chemicals are likely to persist into future industry shifts from regulatory compound use to alternatives such as bisphenol S, diisodecyl, and diisoprenoid phthalates.
The primary data information presented herein reflects a cross-sectional evaluation of environmental toxicants. The effects of long-term exposure to a single toxicant or multiple toxicants at different stages of kidney disease development on longitudinal changes in kidney function have not been elucidated. Longitudinal studies are now needed to guide regulatory strategies to enhance the control or elimination of these molecules to reduce or prevent human exposure and reduce the risk of target organ damage, including kidney.
We recommend that industry, regulators, the Department of Medicine, and the scientific community prospectively implement protocols to ensure the safety of organic contaminants prior to widespread use of these chemicals. Furthermore, ongoing monitoring is needed to detect the occurrence of unanticipated adverse effects.